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Genes (Basel). 2019 Nov 11;10(11). pii: E918. doi: 10.3390/genes10110918.

Restrictive Cardiomyopathy is Caused by a Novel Homozygous Desmin (DES) Mutation p.Y122H Leading to a Severe Filament Assembly Defect.

Author information

1
Erich and Hanna Klessmann Institute for Cardiovascular Research & Development (EHKI), Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum. Georgstrasse 11, D-32545 Bad Oeynhausen, Germany.
2
Otto-von-Guericke University, Magdeburg, Universitätsplatz 2, D-39106 Magdeburg, Germany.
3
Institute for Laboratory and Transfusion Medicine, Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany.
4
Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, AB T2N4Z6, Canada.
5
Comprehensive Heart Failure Center and Department of Internal Medicine I, University Hospital Würzburg, D-97080 Würzburg, Germany.
6
Department of Cardio-Thoracic Surgery, Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum, Georgstrasse 11, 32545 Bad Oeynhausen, Germany.

Abstract

Here, we present a small Iranian family, where the index patient received a diagnosis of restrictive cardiomyopathy (RCM) in combination with atrioventricular (AV) block. Genetic analysis revealed a novel homozygous missense mutation in the DES gene (c.364T > C; p.Y122H), which is absent in human population databases. The mutation is localized in the highly conserved coil-1 desmin subdomain. In silico, prediction tools indicate a deleterious effect of the desmin (DES) mutation p.Y122H. Consequently, we generated an expression plasmid encoding the mutant and wildtype desmin formed, and analyzed the filament formation in vitro in cardiomyocytes derived from induced pluripotent stem cells and HT-1080 cells. Confocal microscopy revealed a severe filament assembly defect of mutant desmin supporting the pathogenicity of the DES mutation, p.Y122H, whereas the wildtype desmin formed regular intermediate filaments. According to the guidelines of the American College of Medical Genetics and Genomics, we classified this mutation, therefore, as a novel pathogenic mutation. Our report could point to a recessive inheritance of the DES mutation, p.Y122H, which is important for the genetic counseling of similar families with restrictive cardiomyopathy caused by DES mutations.

KEYWORDS:

cardiomyopathy; cardiovascular genetics; desmin; desmin-related myopathy; desminopathy; intermediate filaments; restrictive cardiomyopathy

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